Vasileios D. Sioulas

A short narrative review of the feasibility of adopting mild ovarian stimulation for IVF as the current standard of care

IntroductionMild ovarian stimulation has been conceived, proposed and implemented in clinical practice as a safer and cheaper alternative to conventional strategies of controlled ovarian hyperstimulation in preparation for in vitro fertilization (IVF). Our aim was to summarize the key evidence on this topic and explore its possible role as the standard treatment option for women undergoing IVF.Materials and MethodsA short narrative review of the existing literature, with emphasis on mild ovarian stimulation clinical and cost effectiveness, as well as treatment limitations.ResultsNumerous studies highlight mild ovarian stimulation’s favorable characteristics with respect to oocyte/embryo quality, reduced patient risk, and ease of intervention. There is, however, a need for high-quality laboratory environment. Limitations regarding poor responders, older women, or those seeking ovarian stimulation for non-infertility indications should also be considered. Finally, outcomes on the cumulative success rates and the cost effectiveness of mild ovarian stimulation remain inconclusive.ConclusionMild ovarian stimulation protocols for IVF should currently be implemented only in carefully selected populations. Further research is needed to clarify the remaining controversies in this IVF approach.

Comparing classic and newer phenotypes in Greek PCOS women: the prevalence of metabolic syndrome and their association with insulin resistance.

Objective: Recently, it has been debated whether the new polycystic ovary syndrome (PCOS) phenotypes, according to the Rotterdam criteria, share the same metabolic risk with the classic ones (National Institutes of Health 1990). Our study sought to compare the prevalence of metabolic syndrome (MS) and glucose homeostasis disorders in Greek women with classic and new PCOS phenotypes. Materials and methods: Two hundred and sixty-six Greek PCOS women were recruited and divided into groups according to two of the three Rotterdam criteria that they fulfilled. Two subgroups were formed; the first represented the classic phenotypes and the second the new phenotypes. The clinical, biochemical, and ultrasound characteristics of both groups were explored. All subjects were evaluated for MS and underwent a 2-h glucose tolerance test to assess insulin resistance (IR) as measured by the homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUIC-KI), and MATSUDA indices. Results: 62.4% of PCOS women were classified as classic NIH phenotypes of which 32 women had MS (prevalence 19.6%). Only 4 patients categorized in the newer phenotypic groups had MS (prevalence 4.1%). Among the subjects with classic phenotypes, 11.7% exhibited impaired glucose tolerance (3-fold higher percentage compared to patients with newer phenotypes). Regarding IR indices, HOMA-IR was significantly higher and QUICKI significantly lower for classic phenotypes. Conclusions: Greek PCOS women with classic phenotypes are at increased risk for MS and impaired glucose homeostasis compared to women with newer phenotypes. A subclassification of PCOS permits the earlier recognition and closer surveillance of women whose metabolic profile indicates potential risks for adverse health outcomes.

How and when human chorionic gonadotropin curves in women with an ectopic pregnancy mimic other outcomes: differences by race and ethnicity

OBJECTIVE To investigate the hCG profiles in a diverse patient group with ectopic pregnancy (EP) and to understand when they may mimic the curves of an intrauterine pregnancy (IUP) or spontaneous abortion (SAB). DESIGN Retrospective cohort study. SETTING Three university hospitals. PATIENT(S) One hundred seventy-nine women with symptomatic pregnancy of unknown location. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Slope of log hCG; days and visits to final diagnosis. RESULT(S) Of women with an EP, 60% initially exhibited an increase in hCG values, with a median slope of 32% increase in 2 days; 40% of subjects initially had an hCG decrease, with the median slope calculated as a 15% decline in 2 days. In total, the hCG curves in 27% of women diagnosed with EP resembled that of a growing IUP or SAB. Of the EP hCG curves, 16% demonstrated a change in the direction of the slope of the curve. This was more common in African Americans and less evident in Hispanics. Furthermore, it was associated with more clinical visits and days until final diagnosis. CONCLUSION(S) The rate of change in serial hCG values can be used to distinguish EP from an IUP or SAB in only 73% of cases. The number of women who had a change in direction of serial hCG values was associated with race and ethnicity.

The contribution of sildenafil (Viagra) to ovarian stimulation with gonadotropins in a woman with poor ovarian response

Abstract We aim to present the first case of a pregnancy achieved by administering sildenafil (Viagra) to a woman not responding to controlled ovarian hyperstimulation (COH) with the sole use of gonadotropins. A 37-year-old woman underwent COH, as part of an intracytoplasmic sperm injection (ICSI) cycle, with the combination of r-FSH and HMG for 13 d, without evidence of follicular growth. The addition of oral sildenafil at a dose of 50 mg per day for a total of five doses improved the ovarian response and resulted in the retrieval of 10 oocytes. Three embryos were transferred to the uterine cavity resulting in a successful pregnancy and, eventually, the delivery of a healthy neonate. Conclusively, the use of sildenafil as an adjunct to COH protocols may enhance ovarian response in a woman with poor ovarian response (POR) and merits further research.

Uterine rupture at 17 weeks of a twin pregnancy complicated with placenta percreta.

A history of caesarean section is associated with increased risk of abnormal placentation and uterine rupture in the subsequent pregnancies (Daltveit et al. 2008). During their early second trimester, uterine rupture has been, most commonly, recorded as a major adverse event of induced abortions (Levrant et al. 1996). However, in rare occasions, spontaneous uterine rupture has occurred due to the presence of placenta percreta (Endres et al. 2000; Honig et al. 2005). This report presents a case of a second trimester, twin pregnancy complicated with placenta percreta and uterine rupture during the course of miscarriage.

The immunomodulatory and anti-apoptotic effect of dexamethasone in imminent preterm labor: an experimental study.

The study was designed to investigate the effect of dexamethasone (DEX) on the latency period to delivery in a murine model of preterm labor. To this purpose, pregnant mice were randomly assigned in groups: the control group received water for injection (n=20), the preterm labor group was injected with lipopolysaccharide (LPS) (n=22), while the glucocorticoids group was administered DEX either 1h before (n=17) or after (n=7) lipopolysaccharide. In a first set of experiments animals were monitored to record perinatal outcomes. In another set of experiments, the remaining animals were sacrificed eight h after interventions. Fetuses were homogenized to measure tumor necrosis alpha in supernatants. Maternal splenocytes were isolated and stimulated for cytokine production. Serum of mice was incubated with donor cells from healthy pregnant and non-pregnant animals to induce apoptosis. LPS induced preterm labor but treatment or pretreatment with DEX delayed parturition exerting a favorable impact on survival of delivered fetuses. DEX inverted the increase of fetoplacental tumor necrosis alpha levels. Serum of LPS-stimulated mice induced apoptosis of splenocytes of either pregnant or non-pregnant healthy mice; this was reversed after incubation of splenocytes with serum coming from DEX pre-treated mice. The presented findings suggest that DEX administered either as pre-treatment or treatment prolonged gestation and promoted neonatal survival in a sterile murine model of preterm labor. These favorable outcomes were closely linked to alterations in both immune and apoptotic responses of animals.

Controversies in the management of endometriomas in patients undergoing assisted reproduction

IntroductionThe presence of an endometrioma has been proposed to affect the ovarian function in a negative way. Our aim was to present the key evidence on multiple aspects of endometriomas’ management in subfertile couples scheduled for assisted reproduction technologies (ART).Materials and MethodsA critical review of the existing literature was performed focusing on the need of endometrioma treatment prior to ART, the relevant options, the potentially participating surgeon’s characteristics and the socioeconomic perspective.ResultsTo date, we have no definitive data to suggest whether the damage to the ovaries observed in women with endometriomas may be related to the mere presence of the cyst, the surgical procedure to remove it, the combination of the two, or factors currently unknown. Moreover, there is no conclusive evidence that, for subfertile couples, removal of endometriomas increases the chance of having a baby. The uncertainty regarding the best treatment strategy and factors such as the limited number of tertiary centers for laparoscopic surgery throughout the world seems to further complicate the decision.ConclusionsUntil research addresses the current “grey areas”, the management of endometriomas in patients undergoing ART should be individualized and take into consideration numerous parameters.

Parity is associated with lower cervical E-cadherin expression in postmenopausal women.

Aim:  Epithelial cadherin (E‐cadherin), a transmembrane glycoprotein involved in calcium‐dependent homophilic cell‐cell adhesion, is expressed aberrantly during cervical carcinogenesis. E‐cadherin expression and putatively implicated predictors in healthy women remain a rather under‐investigated area. The objective of this study is to evaluate the possible associations between E‐cadherin expression and reproductive/lifestyle factors in cervical epithelial cells from postmenopausal women.

γH2Ax Expression as a Potential Biomarker Differentiating between Low and High Grade Cervical Squamous Intraepithelial Lesions (SIL) and High Risk HPV Related SIL

Background γH2AX is a protein biomarker for double-stranded DNA breakage; its expression was studied in cervical squamous intraepithelial lesions and carcinomas. Methods Immunostaining for phospho-γH2AX was performed in sections from histologically confirmed cervical SIL and carcinomas, as well as from normal cervices used as controls. In total, 275 cases were included in the study: 112 low grade SIL (LGSIL), 99 high grade SIL (HGSIL), 24 squamous cell carcinoma (SCC), 12 adenocarcinoma and 28 cervical specimens with no essential lesions. Correlation of histological grading, high risk vs. low risk HPV virus presence, activated vs. non-activated status (by high risk HPV mRNA expression) and γH2AX expression in both basal and surface segments of the squamous epithelium was performed. Results Gradual increase of both basal and surface γH2AX expression was noted up from normal cervices to LGSIL harboring a low risk HPV type, to LGSIL harboring a high risk virus at a non-activated state (p<0.05). Thereafter, both basal and surface γH2AX expression dropped in LGSIL harboring a high risk virus at an activated state and in HGSIL. Conclusions γH2AX could serve as a potential biomarker discriminating between LGSIL and HGSIL, as well as between LGSIL harboring high risk HPV at an activated state.

Does hormone therapy, tibolone or raloxifene modify VEGF expression in cervical epithelial cells?

ABSTRACT Aim Vascular endothelial growth factor (VEGF) seems to be a critical molecule in cervical carcinogenesis. We aimed to investigate the possible associations between hormonal factors and VEGF expression in cervical epithelial cells from postmenopausal women. Method A total of 105 healthy postmenopausal women (aged 45–68 years old) attending a university menopause clinic were enrolled in this cross-sectional study. Pap smears were derived from current users of 17β-estradiol 1 mg + norethisterone acetate 0.5 mg (n = 28), tibolone 2.5 mg (n = 23), raloxifene HCl 60 mg (n = 21) and women not receiving treatment (n = 33). VEGF immunostaining was evaluated in squamous, glandular and metaplastic cells, using a semiquantitative method (rating scale: 0–3). Results Concerning endogenous hormones, higher Δ4-androstenedione levels were associated with more intense VEGF immunostaining in glandular (p = 0.041) and metaplastic cells (p = 0.004). Hormone therapy and raloxifene did not induce any changes in VEGF immunoreactivity in the examined cells. In contrast, tibolone administration was accompanied by diminished VEGF presence in metaplastic cells (p = 0.016 vs. controls). Conclusion Our findings may in part reflect the molecular processes contributing to the safe profile of hormone therapy, tibolone and raloxifene in cervical carcinogenesis.